NK Cell Activation by Platinum Boosts Immunotherapy in HR + /HER2 − Breast Cancer

ABSTRACT Immunotherapy revolutionizes cancer therapeutics but shows limited efficacy in hormone receptor‐positive (HR + )/human epidermal growth factor receptor 2‐negative (HER2 − ) breast cancer. By leveraging large‐scale multi‐omics and single‐cell RNA sequencing (scRNA‐seq), we characterize the tumor microenvironment of HR + /HER2 − breast cancer, revealing that an abundance of activated natural killer (NK) cells correlates with favorable anti‐PD‐(L)1 responses. Our preclinical models demonstrate that immunotherapy enhances NK cell cytotoxicity and immunomodulatory functions, thereby impeding tumor growth. Furthermore, drug screening of cell lines and patient‐derived tumors reveals that platinum enhances NK cell cytotoxicity, potentially via the NF‐κB pathway, creating synergy with immunotherapy. Consistent with these findings, a clinical cohort analysis shows an increased proportion of activated NK cells in tumors following platinum‐based chemotherapy. Collectively, our study establishes the critical role of NK cells in mediating immunotherapy response in HR + /HER2 − breast cancer and uncovers a novel mechanism whereby platinum agents augment immunotherapeutic efficacy, offering a promising combination strategy.